Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene

Justin A Pater ,Ortal Barel,Chana Vinkler,Anne Griffin,Nicole M Roslin ,Nelly Abdelfatah,Geoffrey Woodland,Zippora Brownstein,Curtis R French ,Karen B Avraham ,Jessica Squires,Jim Houston,Lance P Doucette ,Darren D O’rielly ,Taylor Burt,Fabian Glaser,Cindy Penney,Alexia Hawkey-Noble,Salem Werdyani,Susan G Stanton ,Vincent Denis ,Pascale Marquis,Barbara Vona,Mordechai Shohat,Lara Kamal,Sushma Singh,Touati Benoukraf,Terry‐Lynn Young

doi:10.1007/s00439-022-02444-x

Abstract

Sequencing exomes/genomes have been successful for identifying recessive genes; however, discovery of dominant genes including deafness genes (DFNA) remains challenging. We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Genome-wide SNP genotyping linked SNHL to DFNA33 (LOD = 4.77), a locus on 13q34 previously mapped in a German family with variable SNHL. Whole-genome sequencing identified 51 unremarkable positional variants on 13q34. Continuous clinical ascertainment identified several key recombination events and reduced the disease interval to 769 kb, excluding all but one variant. ATP11A (NC_000013.11: chr13:113534963G>A) is a novel variant predicted to be a cryptic donor splice site. RNA studies verified in silico predictions, revealing the retention of 153 bp of intron in the 3′ UTR of several ATP11A isoforms. Two unresolved families from Israel were subsequently identified with a similar, variable form of SNHL and a novel duplication (NM_032189.3:c.3322_3327+2dupGTCCAGGT) in exon 28 of ATP11A extended exon 28 by 8 bp, leading to a frameshift and premature stop codon (p.Asn1110Valfs43Ter). ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry. Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation. Given that surface PS can be pharmaceutically targeted, hearing loss due to ATP11A could potentially be treated. It is also likely that ATP11A is the gene underlying DFNA33.

Highlights

Hereditary hearing loss is a common sensory disorder exhibiting extensive genetic and clinical heterogeneity (Morton and Nance 2006)
We report the first family, a Canadian family of Northern European descent (NL family) with autosomal dominant sensorineural hearing loss (SNHL) to be linked to DFNA33 since the locus was mapped in 2009 (Bonsch et al 2009)
The intrafamilial variability among individuals in Family A with respect to onset could be explained by (1) large variability in onset of this variant, or (2) the hearing loss not being noticed in younger ages in the older generations as hearing loss starts in high frequencies, not so much affecting speech and normal life, or (3) anticipation revealed in earlier onset from generation to generation

Summary

Introduction

Hereditary hearing loss is a common sensory disorder exhibiting extensive genetic and clinical heterogeneity (Morton and Nance 2006). Over 200 hearing loss genes have been identified (Van Camp and Smith 2015); approximately one-third of the 60 mapped autosomal dominant loci (DFNA) evade discovery. Like other autosomal dominant traits, hearing loss is typically characterized by variable expressivity and reduced penetrance Extended author information available on the last page of the article

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Results

Conclusion